Genetic Variation in the Proximal Promoter of ABC and SLC Superfamilies: Liver and Kidney Specific Expression and Promoter Activity Predict Variation

Abstract

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (−250 to +50 bp) and flanking 5′ sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (π) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.

Gene expression profiling and pathway network analysis of hepatic metabolic enzymes targeted by baicalein

“…Baicalein contains several ortho-hydroxyl substituents on its aromatic rings, which may raise the reactivity and facilitate addition of other substituent such as mercaptans, thereby raising its inducer potencies on expression of phase II enzyme genes. Phase III transporters such as solute carriers group (SLC family) and ATP-binding cassette transporters (ABC family) have a substantial impact on systemic drug exposure and toxicity (Hesselson et al, 2009;Franke et al, 2010). On the other hand, we also observed that the expressions of ESD, DPYD, GSTA1 and SOD1 genes are decreased.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…In addition, noncoding SNPs that regulate drug transporter expression might be particularly important (82,85). These polymorphisms may explain differences in drug response and toxicity among individuals.…”

Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors

“…Variants identified by Sanger sequencing were subsequently genotyped in all 126 DNA samples by MALDI-TOF mass spectrometry, complemented by three previously reported variants in the upstream 5' region of SLC22A9. 13 …”